FDA Accepts Application for Tivozanib in Relapsed/Refractory RCC


The FDA has accepted a new drug application for tivozanib for the treatment of patients with relapsed/refractory renal cell carcinoma.

Michael Bailey

Michael Bailey, associate professor of oncology and urology at Johns Hopkins Medicine

Michael Bailey

The FDA has accepted a new drug application (NDA) for tivozanib (Fotivda) for the treatment of patients with relapsed/refractory renal cell carcinoma (RCC), according to AVEO Oncology, the manufacturer of the next-generation VEGFR-TKI.1

The NDA is primarily based on data from the phase 3 TIVO-3 trial. Results from the study recently presented during the 2020 ASCO Virtual Scientific Program2 showed that tivozanib demonstrated a significant improvement in progression-free survival (PFS) compared with sorafenib (Nexavar), with similar overall survival (OS), in patients with highly relapsed/refractory metastatic RCC.

Results showed that the final hazard ratio (HR) for OS was 0.97 (95% CI, 0.75-1.24; P = .78). Moreover, an updated analysis of the data found that, with a median follow-up of 38 months for tivozanib and 40 months for sorafenib, the median OS was 16.4 months for tivozanib (95% CI, 13.4-22.2) and 19.2 months for sorafenib (95% CI, 15.0-24.2). A subset analysis showed the greatest benefit was derived by the cohort of patients who previously received a checkpoint inhibitor and VEGF inhibitor, with an HR of 0.55, or 2 VEGF TKIs, with an HR of 0.57.

Prior findings showed an increased median PFS for tivozanib when compared with sorafenib at 5.6 months versus 3.9 months, respectively (HR, 0.73; 95% CI, 0.56-0.94; P = .016).

AVEO noted in a press release that the FDA has no current plans to hold a meeting of the Oncologic Drug Advisory Committee to review the NDA. The action date for the NDA is March 31, 2021.

“The acceptance of our NDA filing marks yet another important milestone for AVEO, as we pursue our goal of providing RCC patients whose disease has relapsed or become refractory to multiple lines of therapy with a meaningful new treatment option,” Michael Bailey, president and chief executive officer, AVEO, stated in a press release. “We look forward to working closely with the FDA over the coming months during their review of our application. In parallel, we continue to focus on commercial-readiness to ensure we are well positioned to support the potential launch of tivozanib, subject to approval.”

The TIVO-3 study was a controlled, multicenter, open-label, phase III trial which randomized 350 patients with highly refractory metastatic RCC who had failed ≥2 prior regimens, including VEGF-TKI treatment, 1:1 to receive either oral tivozanib or sorafenib. Crossover between arms was not permitted.

Eighteen percent (n = 31) of patients in the tivozanib arm achieved partial response, compared with 8% (n = 14) of those in the sorafenib arm. The objective response rate was 34% for tivozanib versus 24% for sorafenib.

Treatment with tivozanib was found to be generally well-tolerated, and the safety profile was favorable when compared with sorafenib. Treatment-related adverse events (TRAEs) were reported in 84% (n = 146) of patients receiving tivozanib and 94% (n = 160) of those receiving sorafenib. Serious TRAEs occurred in 11% (n = 19) of patients treated with tivozanib versus 10% (n = 17) of patients who received sorafenib.

The most common grade 3 or 4 AE reported in patients receiving tivozanib and sorafenib was hypertension (21% vs 14%, respectively). The most commonly reported any grade AEs associated with tivozanib were hypertension (38%), diarrhea (33%), fatigue (29%), and decreased appetite (27%).

The investigators reported significantly reduced dose reductions and interruptions due to AEs for tivozanib versus sorafenib (48% vs 63%; P = .0164), despite nearly double the average time of cycles initiated for the tivozanib arm (11.9 months vs 6.7 months, respectively). Treatment related AEs leading to permanent discontinuation were 8% for tivozanib compared with 15% for sorafenib.


  1. AVEO Oncology Announces FDA Acceptance for Filing of a New Drug Application for Tivozanib as a Treatment of Relapsed or Refractory Renal Cell Carcinoma. Published June 1, 2020. https://aveooncology.gcs-web.com/node/14681/pdf. Accessed June 1, 2020.
  2. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). Presented at: 2020 ASCO Virtual Program; May 27, 2020. Abstract 5062.
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